Methods and compositions for sleep disorders and other disorders

ABSTRACT

Use of particular substituted heterocycle fused gamma-carboline compounds as pharmaceuticals and pharmaceutical compositions comprising them for the treatment of one or more disorders involving the 5-HT2A, SERT and/or dopamine D2 pathways are disclosed. In addition, the compounds may be combined with other therapeutic agents for the treatment of one or more sleep disorders, depression, psychosis, dyskinesias, and/or Parkinson&#39;s disease or any combinations.

This application claims the benefit of United States ProvisionalApplication Nos. 61/056,433 filed on May 27, 2008 and 61/155,032 filedon Feb. 24, 2009, both of which applications are hereby incorporated byreference.

TECHNICAL FIELD

The present invention relates to use of particular substitutedheterocycle fused gamma-carbolines as described herein, in free orpharmaceutically acceptable salt forms, as pharmaceuticals andpharmaceutical compositions, e.g., in the treatment of diseasesinvolving 5-HT2A receptor, serotonin transporter (SERT) and/or dopamineD₂ receptor protein phosphorylation pathways, such as depression, sleepdisorders, and mood disorders associated with psychosis or Parkinson'sdisease; psychosis such as schizophrenia associated with depression;bipolar disorder; and other psychiatric and neurological conditions suchas sleep disorders, as well as to combinations with other agents.

BACKGROUND OF THE INVENTION

Psychosis such as schizophrenia is a severe and crippling mentaldisorder that affects about 1% of the population. It is a mentaldisorder that is characterized by gross impairment in reality, majordisturbances in reasoning, often evidenced by delusions andhallucinations, incoherent speech, and/or disorganized and agitatedbehavior. Several classes of anti-psychotic drugs are available fortreatment of schizophrenia, including the prototypical antipsychoticdrugs such as chlorpromazine and haloperidol as well as many others suchas droperidol, fluphenazine, loxapine, mesoridazine molidone,perphenazine, pimozide, prochlorperazine promazine, thioridazine,thiothixene, and trifluoperazine. While these agents are effective intreating positive symptoms of psychosis such as symptoms ofhallucination and delusions, e.g., in schizophrenia, these drugs oftencause both short-term and long-term movement disorders and other sideeffects including acute dystonia (e.g., facial grimacing, torticollis,oculogyric crisis, abnormal contraction of spinal muscles and of musclesinvolved in breathing), akathisia, bradykinesia, rigidity or short termparalysis, parkinsonism, sedation, dry mouth, sexual dysfunction andsometimes tardive dyskinesia. Tardive dyskinesia may persist afterdiscontinuation of the use of typical antipsychotic agents and there isno effective treatment of such side effects. Because of the severity ofthe side effects, typical antipsychotic drugs, though effective intreating the mental and emotional aspect of the disorder, do not helppatients to function normally in society.

Although another class of antipsychotic agents called atypicalantipsychotic agents, which include clozapine, aripiparazole,olanzapine, quetiapine, risperidone and ziprasidone (atypicalantipsychotic agents) are effective in treating positive and negativesymptoms of schizophrenia with fewer extrapyramidal side effects, theseagents can nevertheless cause other serious and at times fatal sideeffects, including bone marrow suppression, seizure, orthostatichypotension, insomnia, sedation, somnolence, weight gain, and ifadministered at higher doses, may again cause extrapyramidal sideeffects. Therefore, atypical antipsychotic agents, though have improvedclinical profiles, are nevertheless undesirable.

In addition to the positive and negative symptoms of psychosis (e.g.,schizophrenia), many psychotic patients often times also suffer fromdepression. While both typical and atypical antipsychotic agents areeffective in treating psychosis, depression is often times neglected orleft under-treated. The combination of psychosis and depression poses aparticular challenge in their treatment as studies revealed that up to10% of the patients suffering from schizophrenia end their own lives.Therefore, there is a need for agents that are useful for the treatmentof psychosis in depressed patients, and for the treatment of depressionas well as other disorders such as sleep and mood disorders in psychoticpatients and patients suffering from Parkinson's disease withoutexhibiting or exhibiting minimal extrapyramidal and other side effectscompared to conventional antipsychotic, hypnotic and anti-depressiveagents.

Substituted heterocycle fused gamma-carbolines are known to be agonistsor antagonists of 5-HT2 receptors, particularly 5-HT2A and 5-HT2Creceptors, in treating central nervous system disorders. These compoundshave been disclosed in U.S. Pat. No. 6,548,493; 7,238,690; 6,552,017;6,713,471; U.S. RE39680, and U.S. RE39679, as novel compounds useful forthe treatment of disorders associated with 5-HT2A receptor modulationsuch as obesity, anxiety, depression, psychosis, schizophrenia, sleepdisorders, sexual disorders migraine, conditions associated withcephalic pain, social phobias, and gastrointestinal disorders such asdysfunction of the gastrointestinal tract motility. PCT/US08/03340 andU.S. application Ser. No. 10/786,935 also disclose methods of makingsubstituted heterocycle fused gamma-carbolines and uses of thesegamma-carbolines as serotonin agonists and antagonists useful for thecontrol and prevention of central nervous system disorders such asaddictive behavior and sleep disorders. Although these referencesdisclose use of substituted heterocycle fused gamma-carbolines toindependently treat disorders associated with serotonin pathways such assleep disorder, depression, psychosis, and schizophrenia associated withthe 5-HT_(2A) pathways, there is no teaching that specific compounds ofsubstituted heterocycle fused gamma-carbolines also exhibit nanomolarbinding affinity to serotonin reuptake transporter (SERT) and dopamineD₂ receptors and therefore may be used to treat a combination ofpsychosis and depressive disorders as well as sleep, depressive and/ormood disorders in patients with psychosis or Parkinson's disease.

In addition to disorders associated with psychosis and/or depression,these references do not disclose use of particular substitutedheterocycle fused gamma-carbolines at a low dose to selectivelyantagonize 5-HT_(2A) receptors without affecting or minimally affectingdopamine D₂ receptors, thereby useful for the treatment of sleepdisorders without the side effects of the dopamine D₂ pathways or sideeffects of other pathways (e.g., GABA_(A) receptors) associated withconvention sedative-hypnotic agents (e.g., benzodiazepines) includingbut not limited to the development of drug dependency, muscle hypotonia,weakness, headache, blurred vision, vertigo, nausea, vomiting,epigastric distress, diarrhea, joint pains, and chest pains.

SUMMARY OF THE INVENTION

It has been discovered that particular substituted heterocycle fusedgamma-carboline compounds (Compounds of Formula I, describedhereinbelow) exhibit unique pharmacological characteristics wherein theypossess high affinity for serotonin 5-HT2A receptors and moderate, yetnanomolar affinity for dopamine receptors and serotonin reuptaketransporter (SERT). The compounds moreover demonstrate selectivitybetween dopamine D 1 and D2 receptors. This is a new and unexpectedbinding profile, which gives the compounds particular utility in certainindications as described below, and in combination therapies.

At low doses, Compounds of Formula I selectively antagonize 5-HT2Areceptors and increases rapid eye movement (REM) and non-REM sleep inanimals. Therefore, at low doses, these compounds may be used to improvesleep maintenance insomnia and insomnia associated with neuropsychiatricand neurologic disorders.

In a clinical trial, low doses (e.g., 1, 5, and 10 mg) of Compounds ofFormula I, e.g. Compound A, dose-dependently increase slow wave sleep,consistent with 5-HT_(2A) receptor antagonism, they dose-dependentlydecreases wake after sleep onset, consistent with improving sleepmaintenance, they increase total sleep time and restore normal sleeparchitecture to patients with insomnia by increasing slow wave sleepearly in the night and increasing stage 2 sleep late in the night,toward morning, they show no early-morning rebound insomnia and did notsuppress REM sleep. They do not impair next-day cognitive function. Themagnitude of WASO decrease and total sleep time increase at 10 mgsuggests the modest D2 (and possibly SERT and D1) occupancy at this dosecontributes favorably to the sleep profile beyond simple 5-HT2A receptorantagonism. Dopamine receptor modulation and SERT inhibition improvepsychiatric symptoms co-morbid with insomnia. Compounds of Formula Irepresent a new approach for treating sleep maintenance insomnia andsleep disorders associated with neuropsychiatric and neurologicaldiseases, as well as for the treatment of sleep disorders,schizophrenia, and other neuropsychiatric and neurological indications.

At higher doses, when 5-HT2A receptors are fully occupied, Compounds ofFormula I modulate dopamine receptor protein phosphorylation. Therefore,Compounds of Formula I are particularly useful for the treatment ofsleep disorders in patients suffering from psychosis such asschizophrenia, Parkinson's disease and/or depression.

Unlike dopamine receptor antagonists, Compounds of Formula I normalizebrain dopamine activity, particularly in the prefrontal cortex. Inaddition, Compounds of Formula I also moderately bind to SERT.Therefore, Compounds of Formula I are particularly useful for thetreatment of psychosis in patients suffering from depression. Unlikemany traditional antipsychotic drugs, Compounds of Formula I show animproved selectivity profile with respect to off-target interactionssuch as adrenergic alpha-la, serotonin 5-HT2C, and histamine H1associated with many side effects compared to other antipsychotic drugs.Compounds of Formula I are therefore also useful as antipsychotic agentsin patients who are unable to tolerate the side effects of conventionantipsychotic drugs.

In addition to binding to 5-HT2A and dopamine D₂ receptors, Compounds ofFormula I also exhibit nanomolar binding affinity for SERT compared toknown antidepressants. Therefore, Compounds of Formula I are useful forthe treatment of depression in patients suffering from psychosis.

Because Compounds of Formula I have a wider separation between 5-HT_(2A)and D₂ receptor affinities than other atypical antipsychotic drugs (˜60fold), they are additionally useful in reduction of dyskinesia. Forexample, they reduce L-DOPA-induced dyskinetic behavior in a mousemodel. Without intending to be bound by theory, it is hypothesized thatthis is accomplished by virtue of the potent 5-HT_(2A) antagonism withminimal interference with L-DOPA-induced motor correction, by virtue ofthe low relative D₂ receptor activity. Parkinson's disease results fromloss of DA neurons in the substantia nigra pars compacta. The primarymotor symptoms of PD are treated by L-DOPA. Activation of medium spinyneurons in the dorsolateral striatum that project to the substantianigra pars reticulata results in disinhibition of thalamocorticalneurons and increased motor activity. Overactivity of this “direct”striatal pathway may contribute to the expression of dyskinesias, suchas are commonly seen in PD patients being treated with dopaminergicdrugs such as L-dopa. 5-HT_(2A) receptors are localized in striatalmedium spiny neurons. Compounds of Formula I are thus believed to blockdyskinesias by blockade of 5-HT_(2A) receptors.

Therefore, the invention provides methods as follows:

A method (Method I) for the treatment of one or more disorders involvingserotonine 5-HT_(2A), dopamine D2 and/or serotonin reuptake transporter(SERT) pathway, comprising administering to a patient in need thereof aCompound of Formula I:

wherein X is O, —NH or —N(CH₃); and Y is —O— or —C(O)—, in free orpharmaceutically acceptable salt form, at a dose which selectivelyblocks 5-HT_(2A) receptors.

The invention further provides Method I as follows:

-   -   1.1 Method I comprising a compound of Formula I, wherein X is        —N(CH₃);    -   1.2 Method I comprising a compound of Formula I, wherein X is        —NH;    -   1.3 Method I comprising a compound of Formula I, wherein X is O;    -   1.4 Method I or any of 1.1-1.3, comprising a compound of Formula        I, wherein Y is —C(O)—;    -   1.5 Method I or any of 1.1-1.3, comprising a compound of Formula        1, wherein Y is —O—;    -   1.6 any of the preceding methods wherein the Compound of Formula        I is selected from a group consisting of:

-   -   1.7 any of the preceding methods wherein the Compound of Formula        I is:

-   -   1.8 any of the preceding methods wherein the Compound of Formula        I is:

-   -   1.9 any of the preceding methods wherein the Compound of Formula        I is:

-   -   1.10 any of the preceding methods wherein the Compound of        Formula I is:

-   -   1.11 any of the preceding methods wherein the Compound of        Formula I is:

-   -   1.12 any of the preceding methods wherein the Compound of        Formula I is:

-   -   1.13 any of the preceding methods wherein the Compounds of        Formula I (i) bind to 5-HT2A receptors, e.g., with a K_(i) of        less than 50 nM, more preferably less 10 nM, still more        preferably less than 5 nM, most preferably less than 1 nM;        and (ii) also bind to dopamine D₂ receptors and SERT, e.g., with        a K_(i) of less than 100 nM, preferably less than 75 nM, more        preferably less 50 nM, in a binding assay as described in        Example 1 below;    -   1.14 any of the preceding methods wherein the Compounds of        Formula I (i) bind to 5-HT2A, e.g., with a K_(i) of less than 5        nM, preferably less than 1 nM, and (ii) also bind to dopamine D₂        receptors and SERT, e.g., with a K_(i) of less than 100 nM,        preferably less than 75 nM, more preferably less than 50 nM in a        binding assay as described in Example 1 below;    -   1.15 any of the preceding methods wherein the Compounds of        Formula I (i) bind to 5-HT2A, e.g., with a K_(i) of less than 1        nM and (ii) bind to dopamine D₂ receptors, e.g., with a K_(i) of        about 25-75 nM; and (iii) also bind to SERT, e.g., with a K_(i)        of less than 100 nM, preferably less than 75 nM, more preferably        less 50 nM, in a binding assay as described in Example 1 below;    -   1.16 any of the preceding methods wherein the Compounds of        Formula I does not bind to adrenergic alpha-1a receptors (α1A)        or bind to a1A receptors, e.g., with a K_(i) of greater than 75        nM, preferably greater than 100 nM in a binding assay as        described in Example 1 below;    -   1.17 any of the preceding methods wherein the Compounds of        Formula I does not bind to 5-HT2C receptors, or bind to 5-HT2C        receptors e.g., with a K_(i) of greater than 75 nM, preferably        greater than 100 nM, more preferably greater than 150 nM in a        binding assay as described in Example 1 below;    -   1.18 any of the preceding methods wherein the Compounds of        Formula I does not bind to H1 receptors, or bind to H1        receptors, e.g., with a K_(i) of greater than 500 nM, preferably        greater than 750 nM, more preferably greater than 1000 nM in a        binding assay as described in Example 1 below;    -   1.19 any of the preceding methods wherein the Compounds of        Formula I (i) bind to 5-HT_(2A), e.g., with a K_(i) of less than        5 nM, preferably less than 1 nM, (ii) bind to dopamine D₂        receptors, e.g., with a K_(i) of 25-75 nM; (iii) bind to SERT,        e.g., with a K_(i) of less than 100 nM, preferably less than 75        nM, more preferably less 50 nM; and (iv) does not bind to α1A,        5-HT2C and/or H1 receptors, or bind to α1A, 5-HT2C and/or H1        receptors e.g., with a K_(i) of greater than 75 nM in a binding        assay as described in Example 1 below;    -   1.20 any of the preceding methods wherein said one or more        disorders are selected from (1) psychosis, e.g., schizophrenia,        in a patient suffering from depression; (2) depression in a        patient suffering from psychosis, e.g., schizophrenia; (3) mood        disorders associated with psychosis, e.g., schizophrenia, or        Parkinson's disease; and (4) sleep disorders associated with        psychosis, e.g., schizophrenia, or Parkinson's disease;    -   1.21 Method I or any of 1.1-1.20, wherein said disorder is        psychosis, e.g., schizophrenia and said patient is a patient        suffering from depression;    -   1.22 Method I or any of 1.1-1.21, wherein said patient is unable        to tolerate the side effects of convention antipsychotic drugs,        e.g., chlorpromazine, haloperidol droperidol, fluphenazine,        loxapine, mesoridazine molidone, perphenazine, pimozide,        prochlorperazine promazine, thioridazine, thiothixene,        trifluoperazine, clozapine, aripiparazole, olanzapine,        quetiapine, risperidone and ziprasidone;    -   1.23 Method I or any of 1.1-1.21, wherein said patient is unable        to tolerate the side effects of convention antipsychotic drugs,        e.g., haloperidol, aripiparazole, clozapine, olanzapine,        quetiapine, risperidone, and zipasidone;    -   1.24 Method I or any of 1.1-1.20, wherein said disorder is        depression and said patient is a patient suffering from        psychosis, e.g., schizophrenia, or Parkinson's disease;    -   1.25 Method I or any of 1.1-1.20, wherein said one or more        disorders is sleep disorder and said patient is suffering from        depression;    -   1.26 Method I or any of 1.1-1.20, wherein said one or more        disorders is sleep disorder and said patient is suffering from        psychosis, e.g., schizophrenia;    -   1.27 Method I or any of 1.1-1.20, wherein said one or more        disorders is sleep disorder and said patient is suffering from        Parkinson's disease;    -   1.28 Method I or any of 1.1-1.20 or 1.25-1.27, wherein said one        or more disorders is sleep disorder and said patient is        suffering from depression and psychosis, e.g., schizophrenia, or        Parkinson's disease;    -   1.29 Any of the foregoing methods, wherein the effective amount        is an amount sufficient to bind to SERT, 5-HT2A and D₂        receptors, e.g., with a K_(i) of less than 100 nM, preferably        less than 75 nM, more preferably less than 50 nM in an assay as        described in Example 1 below;    -   1.30 Any of the foregoing methods, wherein the effective amount        is an amount sufficient to (i) bind to SERT, 5-HT2A and D₂        receptors, e.g., with a K_(i) of less than 100 nM, preferably        less than 75 nM, more preferably less than 50 nM, and (ii) does        not bind to α1A, 5-HT2C and/or H1 receptors or bind to α1A,        5-HT2C and/or H1 receptors, e.g., with a K_(i) of greater than        50 nM, preferably greater than 75 nM in a binding assay as        described in Example 1 below;    -   1.31 Any of the foregoing methods, wherein the effective amount        is an amount sufficient to bind to 5-HT2A, e.g., with a K_(i) of        less than 5 nM, preferably less than 1 nM, and also bind to        dopamine D₂ receptors and SERT, e.g., with a K_(i) of less than        100 nM, preferably less than 75 nM, more preferably less than 50        nM in a binding assay as described in Examples 1 below;    -   1.32 Any of the foregoing methods, wherein the effective amount        is an amount sufficient to (i) bind to 5-HT2A, e.g., with a        K_(i) of less than 5 nM, preferably less than 1 nM; (ii) bind to        dopamine D₂ receptors, e.g., with a K_(i) of 25-75 nM; (iii)        bind to SERT, e.g., with a K_(i) of less than 100 nM, preferably        less than 75 nM, more preferably less than 50 nM; and (iv) does        not bind to α1A, 5-HT2C and/or H1 receptors, or bind to α1A,        5-HT2C and/or H1 receptors, e.g., with a K_(i) of greater than        50 nM, preferably greater than 75 nM in a binding assay as        described in Examples 1 below;    -   1.33 Any of the foregoing methods, wherein the ratio of the        K_(i) of dopamine D₂ to the K_(i) of 5-HT2A is greater than 25,        preferably greater than 50;    -   1.34 Any of the foregoing methods, wherein ratio of the K_(i) of        α1A to the K_(i) of 5-HT2A is greater than 25, preferably        greater than 50, more preferably greater than 100, most        preferably greater than 125;    -   1.35 Any of the foregoing methods, wherein ratio of the K_(i) of        5HT2C to the K_(i) of 5-HT2A is greater than 150, more        preferably greater than 300;    -   1.36 Any of the foregoing methods, wherein ratio of the K_(i) of        H1 to the K_(i) of 5-HT2A is greater than 100, more preferably        greater than 200;    -   1.37 Any of the foregoing methods, wherein the effective amount        is 1 mg-100 mg, preferably 2.5-50 mg.    -   1.38 Any of the foregoing methods wherein a condition to be        treated is dyskinesia, e.g. in a patient receiving dopaminergic        medications, e.g., medications selected from levodopa and        levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B        inhibitors), dopamine agonists, and anticholinergics, e.g.,        levodopa.    -   1.39 Any of the foregoing methods wherein the patient suffers        from Parkinson's disease.

A method (Method II) for the treatment of one or more sleep disorderscomprising administering to a patient in need thereof a Compound ofFormula I:

wherein X is O, —NH or —N(CH₃); and Y is —O— or —C(O)—, in free orpharmaceutically acceptable salt form, at a dose selective for 5-HT_(2A)receptor blockade, e.g. a daily dose of 0.1-20 mg, e.g., 0.5-10 mg.

The invention further provides Method II as follows:

-   -   2.1 Method II comprising a compound of Formula I, wherein X is        —N(CH₃);    -   2.2 Method II comprising a compound of Formula I, wherein X is        —NH;    -   2.3 Method II comprising a compound of Formula I, wherein X is        O;    -   2.4 Method II or any of 2.1-2.3, comprising a compound of        Formula I, wherein Y is —C(O)—;    -   2.5 Method II or any of 2.1-2.3, comprising a compound of        Formula I, wherein Y is —O—;    -   2.6 any of the preceding methods wherein the Compound of Formula        I is selected from a group consisting of:

-   -   2.7 any of the preceding methods wherein the Compound of Formula        I is:

-   -   2.8 any of the preceding methods wherein the Compound of Formula        I is:

-   -   2.9 any of the preceding methods wherein the Compound of Formula        I is:

-   -   2.10 any of the preceding methods wherein the Compound of        Formula I is:

-   -   2.11 any of the preceding methods wherein the Compound of        Formula I is:

-   -   2.12 any of the preceding methods wherein the Compound of        Formula I is:

-   -   2.13 any of the preceding methods wherein the Compounds of        Formula I (i) bind to 5-HT2A, e.g., with a K_(i) of less than 25        nM, preferably less than 10 nM, more preferably 1 nM; and (ii)        does not bind to D₂ receptors and/or SERT or bind to dopamine D₂        receptors and/or SERT, e.g., with a K_(i) of greater than 50 nM,        preferably greater than 75 nM, more preferably greater than 100        nM, in a binding assay as described in the Example 1 below;    -   2.14 any of the preceding methods wherein the Compounds of        Formula I (i) bind to 5-HT2A, e.g., with a K_(i) of less than 5        nM, preferably less than 1 nM, and does not bind or only bind to        dopamine D₂ receptors, SERT, α1A, 5-HT2C or H1 receptors, e.g.,        with a K_(i) of greater than 50 nM, preferably greater than 75        nM, more preferably greater than 100 nM, in a binding assay as        described in example 1 below;    -   2.15 Any of the foregoing methods, wherein the effective amount        to treat one or more sleep disorders is an amount sufficient to        bind to 5-HT2A receptors, e.g., with a K_(i) of less than 25 nM,        preferably less than 10 nM, more preferably 1 nM, but does not        bind to D₂ receptors and/or SERT or bind to D₂ receptors and/or        SERT, e.g., with a K_(i) of greater than 50 nM, preferably        greater than 75 nM, more preferably greater than 100 nM in an        assay as described in Example 1 below;    -   2.16 Any of the foregoing methods, wherein the sleep disorder        include sleep maintenance insomnia, frequent awakenings, and        waking up feeling unrefreshed;    -   2.17 Any of the foregoing methods, wherein the sleep disorder is        sleep maintenance insomnia;    -   2.18 Any of the foregoing methods, wherein the effective amount        is 1 mg-5 mg, preferably 2.5-5 mg;    -   2.19 Any of the foregoing methods, wherein the effective amount        is 2.5 or 5 mg.    -   2.20 Any of the foregoing methods wherein the sleep disorder is        in a patient suffering from or at risk of dyskinesia, e.g., a        patient receiving dopaminergic medications, e.g., selected from        levodopa and levodopa adjuncts (carbidopa, COMT inhibitors,        MAO-B inhibitors), dopamine agonists, and anticholinergics,        e.g., receiving levodopa.    -   2.21 Any of the foregoing methods wherein the patient suffers        from Parkinson's disease.

Compounds of the Invention may exist in free or salt form, e.g., as acidaddition salts. In this specification unless otherwise indicatedlanguage such as Compounds of the Invention is to be understood asembracing the compounds in any form, for example free or acid additionsalt form, or where the compounds contain acidic substituents, in baseaddition salt form. The Compounds of the Invention are intended for useas pharmaceuticals, therefore pharmaceutically acceptable salts arepreferred. Salts which are unsuitable for pharmaceutical uses may beuseful, for example, for the isolation or purification of free Compoundsof the Invention or their pharmaceutically acceptable salts, aretherefore also included. Pharmaceutically acceptable salts include, forexample, the hydrochloride and tosylate salts. Where dosage amounts ofsalts are given by weight, e.g., milligrams per day or milligrams perunit dose, the dosage amount of the salt is given as the weight of thecorresponding free base, unless otherwise indicated.

The invention also provides the foregoing methods, e.g., Method I, e.g.,any of 1.1-1.39, or Method II, e.g., any of 2.1-2.19, wherein theCompound of Formula I, in free or pharmaceutically acceptable salt formis administered in a composition, wherein said Compound of Formula I infree or pharmaceutically acceptable salt form in admixture with apharmaceutically acceptable diluent or carrier.

The invention further provides a Pharmaceutical Composition (CompositionI) comprising a Compound of Formula I in free or pharmaceuticallyacceptable salt form, e.g., as described in any of Methods I or1.1-1.37, in admixture with a pharmaceutically acceptable diluent orcarrier for use in any of Methods I or 1.1-1.37.

The invention further provides a Pharmaceutical Composition (CompositionII) comprising a Compound of Formula I in free or pharmaceuticallyacceptable salt form, e.g., as described in any of Method II, e.g., anyof 2.1-2.19, in admixture with a pharmaceutically acceptable diluent orcarrier for use in any of Method II, e.g., any of 2.1-2.19.

In another aspect, the invention provides use of a Compound of Formula Ior a pharmaceutical composition comprising a Compound of formula I infree or pharmaceutically acceptable salt form as described in Methods 1or 1.1-1.37, in the manufacture of a medicament for the treatment of oneor more disorders involving serotonin 5-HT2A, dopamine D₂ and/orserotonin reuptake transporter (SERT) pathway as described in any ofMethods I or 1.1-1.37.

In another aspect, the invention provides use of a Compound of Formula Ior a pharmaceutical composition comprising a Compound of formula I infree or pharmaceutically acceptable salt form as described in Methods IIor 2.1-2.19, in the manufacture of a medicament for the treatment of oneor more sleep disorders as described in any of Methods II or 2.1-2.19.

In another aspect, methods which involve use of a Compound of Formula Ior a pharmaceutical composition comprising a Compound of Formula I infree or pharmaceutically acceptable salt form as described in MethodsI-A or II-A, for the treatment of sleep disorders, depression,pyschosis, or any combinations thereof, in patients suffering from thelisted diseases and/or Parkinson's disease, as described in any ofMethods I-A or II-A, or 3.1-3.34.

DETAILED DESCRIPTION OF THE INVENTION Methods of Making Compounds of theInvention

The compounds of the formula I and their pharmaceutically acceptablesalts may be made using the methods as described and exemplified in anyof the following patents or applications: U.S. Pat. No. 6,548,493;7,238,690; 6,552,017; 6,713,471; U.S. RE39680; U.S. RE39679;PCT/US08/03340; U.S. application Ser. No. 10/786,935; and U.S.Provisional Application No. 61/036,069. If not commercially available,starting materials for these processes may be made by procedures, whichare selected from the chemical art using techniques which are similar oranalogous to the synthesis of known compounds. All references citedherein are hereby incorporated in their entirety by reference.

The words “treatment” and “treating” are to be understood accordingly asembracing prophylaxis and treatment or amelioration of symptoms ofdisease as well as treatment of the cause of the disease.

The term “patient” may include a human or non-human patient.

Compounds of the Invention refer to Compounds of Formula I, whichinclude:

in free or pharmaceutically acceptable salt form. Compounds of theinvention are useful in any of Method I, or 1.1-1.37, particularlyuseful for the treatment of (1) sleep disorder, e.g., sleep maintenanceinsomnia; (2) depression in patients suffering from psychosis orParkinson's disease; (3) psychosis, e.g., schizophrenia, in a patientsuffering from depression; or (4) mood disorder associated withpsychosis, e.g., schizophrenia, or Parkinson's disease. Compounds of theinvention are also useful for any of Method II or 2.1-2.19, particularlyfor the treatment of sleep disorder, e.g., sleep maintenance insomnia.

The phrase “depression in a patient suffering from psychosis” mayinclude depressed patients suffering from a co-morbid psychotic disordersuch as schizophrenia or it may include psychotic depressed patientswherein such patients suffer from severe depression wherein suchdepression accompanies hallucinations and/or delusions.

The term “sleep maintenance insomnia” refers to the inability to stayasleep or to resume sleep after waking in the middle of the sleep cycle.

The terms “Compounds of Formula I” and “Compounds of the Invention” maybe used interchangeably and may be used as a sole therapeutic agent, orthey may also be used in combination or for co-administration with otheractive agents.

The discovery of the selective receptor profiles of the Compounds ofFormula I not only provides effective treatment of 5-HT2A, SERT and/orD₂ receptor related disorders without or with minimal extrapyramidalside effects as claimed in the current invention, but also providesinsight for the design of a combination therapy for the treatment ofrelated disorders, wherein a Compound of Formula I may be used incombination with second therapeutic agents, particularly at lowerdosages than when the individual agents are used as a monotherapy so asto enhance the therapeutic activities of the combined agents withoutcausing the undesirable side effects commonly occur in conventionalmonotherapy. For example, as Compounds of the Invention bind to 5-HT2A,D₂ and/or SERT and are useful for treating patients with a combinationof disorders, e.g., (a) psychosis with a co-morbid disorder ofdepression and/or sleep disorder; (b) depression with a co-morbiddisorder of psychosis; (c) sleep disorder in patients suffering frompsychosis, Parkinson disease, and/or depression; or (d) any combinationsthereof, Compounds of Formula I may be simultaneously, sequentially, orcontemporaneously administered with other anti-depressant,anti-psychotic, other hypnotic agents, and/or agents use to treatParkinson's disease or mood disorders. In another example, side effectsmay be reduced or minimized by administering a Compound of Formula I incombination with one or more second therapeutic agents in free or saltform, wherein the dosages of the second therapeutic agent(s) or bothCompound of Formula I and the second therapeutic agents are lower thanif the agents/compounds are administered as a monotherapy.

In a particular embodiment, the Compounds of Formula I are useful totreat dyskinesia in a patient receiving dopaminergic medications, e.g.,selected from levodopa and levodopa adjuncts (carbidopa, COMTinhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics,e.g., such as are used in the treatment of Parkinson's disease.

As demonstrated above, Compounds of Formula I have a wide separationbetween 5-HT_(2A) and D₂ receptor affinities than other atypicalantipsychotic drugs (˜60 fold). They reduce L-DOPA-induced dyskineticbehavior. Without intending to be bound by theory, it is hypothesizedthat this is accomplished by virtue of the potent 5-HT_(2A) antagonismwith minimal interference with L-DOPA-induced motor correction, byvirtue of the low relative D₂ receptor activity. Parkinson's diseaseresults from loss of DA neurons in the substantia nigra pars compacta.The primary motor symptoms of PD are treated by L-DOPA. Activation ofmedium spiny neurons in the dorsolateral striatum that project to thesubstantia nigra pars reticulata results in disinhibition ofthalamocortical neurons and increased motor activity. Overactivity ofthis “direct” striatal pathway may contribute to the expression ofdyskinesias. 5-HT_(2A) receptors are localized in striatal medium spinyneurons. Compounds of Formula I are thus believed to block dyskinesiasby blockade of 5-HT_(2A) receptors.

In another aspect of the current invention, Method I, e.g., any of1.1-1.37, or Method II, e.g., any of 2.1-2.19, further comprises one ormore therapeutic agents selected from compounds that modulate GABAactivity (e.g., enhances the activity and facilitates GABAtransmission), a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT1aagonist, a 5-HT2a antagonist, a 5-HT2a inverse agonist, etc.), amelatonin agonist, an ion channel modulator (e.g., blocker), aserotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin receptorantagonist, an H3 agonist, a noradrenergic antagonist, a galaninagonist, a CRH antagonist, human growth hormone, a growth hormoneagonist, estrogen, an estrogen agonist, a neurokinin-1 drug, ananti-depressant, and an antipsychotic agent, e.g., an atypicalantipsychotic agent, in free or pharmaceutically acceptable salt form(Method I-A and II-A respectively).

In a further embodiment of this aspect, the invention provides MethodI-A or II-A as follows, further comprising one or more therapeuticagents.

-   -   3.1 Method I-A or II-A, wherein the therapeutic agent(s) is        compounds that modulate GABA activity (e.g., enhances the        activity and facilitates GABA transmission);    -   3.2 Method I-A or II-A or 3.1, wherein the GABA compound is        selected from a group consisting of one or more of doxepin,        alprazolam, bromazepam, clobazam, clonazepam, clorazepate,        diazepam, flunitrazepam, flurazepam, lorazepam, midazolam,        nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam;    -   3.3 Method I-A or II-A, wherein the therapeutic agent is an        additional 5HT2a antagonist;    -   3.4 Method I-A or II-A or 3.3, wherein said additional 5HT2a        antagonist is selected from one or more of ketanserin,        risperidone, eplivanserin, volinanserin (Sanofi-Aventis,        France), pruvanserin, MDL 100907 (Sanofi-Aventis, France),        HY10275 (Eli Lilly), APD125 (Arena Pharmaceuticals, San Diego,        Calif.), and AVE8488 (Sanofi-Aventis, France);    -   3.5 Method I-A or II-A, wherein the therapeutic agent is a        melatonin agonist;    -   3.6 Method I-A or II-A or 3.5, wherein the melatonin agonist is        selected from a group consisting of one or more of melatonin,        ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan), VEC-162        (Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Phase II        Discovery) and agomelatine;    -   3.7 Method I-A or II-A, wherein the therapeutic agent is an ion        channel blocker;    -   3.8 Method I-A or II-A or 3.7, wherein said ion channel blocker        is one or more of lamotrigine, gabapentin and pregabalin.    -   3.9 Method I-A or II-A, wherein the therapeutic agent is an        orexin receptor antagonist;    -   3.10 Method I-A or II-A or 3.9, wherein the orexin receptor        antagonist is selected from a group consisting of orexin, a        1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868        (GlaxoSmithKline) and a benzamide derivative;    -   3.11 Method I-A or II-A, wherein the therapeutic agent is the        serotonin-2 antagonist/reuptake inhibitor (SARI);    -   3.12 Method I-A or II-A or 3.11, wherein the serotonin-2        antagonist/reuptake inhibitor (SARI) is selected from a group        consisting of one or more Org 50081 (Organon-Netherlands),        ritanserin, nefazodone, serzone and trazodone;    -   3.13 Method I-A or II-A, wherein the therapeutic agent is the        5HT1a agonist;    -   3.14 Method I-A or II-A or 3.13, wherein the 5HT1a agonist is        selected from a group consisting of one or more of repinotan,        sarizotan, eptapirone, buspirone and MN-305 (MediciNova, San        Diego, Calif.);    -   3.15 Method I-A or II-A, wherein the therapeutic agent is the        neurokinin-1 drug;    -   3.16 Method I-A or II-A or 3.15, wherein the neurokinin-1 drug        is Casopitant (GlaxoSmithKline);    -   3.17 Method I-A or II-A, wherein the therapeutic agent is an        antipsychotic agent;    -   3.18 Method I-A or II-A or 3.17, wherein the antipsychotic agent        is selected from a group consisting of chlorpromazine,        haloperidol, droperidol, fluphenazine, loxapine, mesoridazine        molidone, perphenazine, pimozide, prochlorperazine promazine,        thioridazine, thiothixene, trifluoperazine, clozapine,        aripiparazole, olanzapine, quetiapine, risperidone, ziprasidone        and paliperidone;    -   3.19 Method I-A or II-A, wherein the therapeutic agent is an        anti-depressant;    -   3.20 Method I-A or H-A or 3.19, wherein the anti-depressant is        selected from amitriptyline, amoxapine, bupropion, citalopram,        clomipramine, desipramine, doxepin, duloxetine, escitaloprame,        fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline,        mirtazapine, nefazodone, nortriptyline, paroxetine, phenlzine        sulfate, protiptyline, sertraline, tranylcypromine, trazodone,        trimipramine, and velafaxine;    -   3.21 Method I-A or II-A, 3.17 or 3.18, wherein the antipsychotic        agent is an atypical antipsychotic agent;    -   3.22 Method I-A or II-A, or any of 3.17-3.21, wherein the        atypical antipsychotic agent is selected from a group consisting        of clozapine, aripiparazole, olanzapine, quetiapine,        risperidone, ziprasidone, and paliperidone;    -   3.23 Method I-A or II-A, wherein the therapeutic agent is        selected from any of methods 3.1-3.22, e.g., selected from a        group consisting of modafinil, armodafinil, doxepin, alprazolam,        bromazepam, clobazam, clonazepam, clorazepate, diazepam,        flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,        oxazepam, temazapam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam,        ketanserin, risperidone, eplivanserin, volinanserin        (Sanofi-Aventis, France), pruvanserin, MDL 100907        (Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (Arena        Pharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis,        France), repinotan, sarizotan, eptapirone, buspirone, MN-305        (MediciNova, San Diego, Calif.), melatonin, ramelteon (ROZEREM®,        Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals,        Rockville, Md.), PD-6735 (Phase II Discovery), agomelatine,        lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea,        SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a        benzamide derivative, Org 50081 (Organon-Netherlands),        ritanserin, nefazodone, serzone, trazodone, Casopitant        (GlaxoSmithKline), amitriptyline, amoxapine, bupropion,        citalopram, clomipramine, desipramine, doxepin, duloxetine,        escitaloprame, fluoxetine, fluvoxamine, imipramine,        isocarboxazid, maprotiline, mirtazapine, nefazodone,        nortriptyline, paroxetine, phenlzine sulfate, protiptyline,        sertraline, tranylcypromine, trazodone, trimipramine,        velafaxine, chlorpromazine, haloperidol, droperidol,        fluphenazine, loxapine, mesoridazine molidone, perphenazine,        pimozide, prochlorperazine promazine, thioridazine, thiothixene,        trifluoperazine, clozapine, aripiparazole, olanzapine,        quetiapine, risperidone, ziprasidone and paliperidone;    -   3.24 Method I-A or II-A, wherein the therapeutic agent is an H3        agonist;    -   3.25 Method I-A or II A, wherein the therapeutic agent is an H3        antagonist;    -   3.26 Method I-A or II-A, wherein the therapeutic agent is a        noradrenergic antagonist;    -   3.27 Method I-A or II-A, wherein the therapeutic agent is a        galanin agonist;    -   3.28 Method I-A or II-A, wherein the therapeutic agent is a CRH        antagonist;    -   3.29 Method I-A or II-A, wherein the therapeutic agent is a        human growth hormone;    -   3.30 Method I-A or II-A, wherein the therapeutic agent is a        growth hormone agonist;    -   3.31 Method I-A or II-A, wherein the therapeutic agent is        estrogen;    -   3.32 Method I-A or II-A, wherein the therapeutic agent is an        estrogen agonist;    -   3.33 Method I-A or II-A, wherein the therapeutic agent is a        neurokinin-1 drug;    -   3.34 Method I-A or II-A, wherein a therapeutic agent is combined        with compounds of Formula (I) and the therapeutic agent is an        anti-Parkinson agent such as L-dopa, co-careldopa, duodopa,        stalova, symmetrel, benzotropine, biperiden, bromocryiptine,        entacapone, pergolide, pramipexole, procyclidine, ropinirole,        selegiline and tolcapone.    -   3.35 Method I-A or II-A, wherein compounds of Formula (I) may be        used to treat sleep disorders, depression, pyschosis, or any        combinations thereof, in patients suffering from the listed        diseases and/or Parkinson's disease.    -   3.36 Method I-A or II-A, wherein the disorder is selected from        at least one or more of psychosis, e.g., schizophrenia,        depression, mood disorders, sleep disorders (e.g., sleep        maintenance and/or sleep onset) or any combination of disorders        thereof;    -   3.37 Any of the foregoing methods wherein the disorder is sleep        disorder;    -   3.38 Any of the foregoing methods, wherein the disorder is sleep        disorder associated with psychosis, e.g., schizophrenia or        Parkinson's disease; in free or pharmaceutically acceptable salt        form.

In another aspect of the invention, the combination of a Compound ofFormula I and one or more second therapeutic agents as described inMethods I-A, II-A or any of 3.1-3.23, may be administered as acomposition. The combination compositions can include mixtures of thecombined drugs, as well as two or more separate compositions of thedrugs, which individual compositions can be, for example,co-administered together to a patient.

The person of skill in the art, in possession at the receptor bindingprofile of the Compounds of Formula I together with those of otherdrugs, can design combination therapies having optimal receptor activityto enhance efficacy and reduce side effects.

In a particuar embodiment, Method I-A and Method II-A comprisesadministering to a patient in need thereof, a Compound of Formula I incombination with an atypical antipsychotic agent, e.g., a compoundselected from clozapine, aripiparazole, olanzapine, quetiapine,risperidone, ziprasidone, or paliperidone, in free or pharmaceuticallyacceptable salt form, for example wherein the dosage of the atypicalantipsychotic agent is reduced and/or side effects are reduced.

In another embodiment, Method I-A and Method II-A comprisesadministering to a patient in need thereof, a Compound of Formula I incombination with an anti-depressant, e.g., amitriptyline, amoxapine,bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine,escitaloprame, fluoxetine, fluvoxamine, imipramine, isocarboxazid,maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine,phenlzine sulfate, protiptyline, sertraline, tranylcypromine, trazodone,trimipramine, or velafaxine, in free or pharmaceutically acceptable saltform.

Alternatively, the anti-depressant may be used as an adjunct medicationin addition to the compound of Formula I.

In still another embodiment, Method I-A or II-A comprises administeringto a patient in need thereof, a Compound of Formula I in combinationwith a compound that modulates GABA activity, e.g., a compound selectedfrom doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate,diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,oxazepam, temazapam, triazolam, indiplon, zopiclone, eszopiclone,zaleplon, Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT 201 (EvotecPharmaceuticals), estazolam or any combinations thereof, in free orpharmaceutically acceptable salt form. In another preferred embodiment,Method I-A or II-A comprises administering to a patient in need thereof,a Compound of Formula I in combination with doxepin in free orpharmaceutically acceptable salt form. Dosages of doxepin can vary inany range known to a person of ordinary skill in the art. In oneexample, a 10 mg dose of doxepin may be combined with any dosage of acompound of Formula I.

In another embodiment, Method I-A or II-A comprises administering to apatient in need thereof, a Compound of Formula I in combination(including as part of a daily dosage regimen) with an atypicalstimulant, e.g., a modafinil, adrafinil, or armodafinil. A regiminincorporating a Compound of Formula I with such drugs promotes moreregular sleep, and avoids side effects such as psychosis or maniaassociated with higher levels of such drugs, e.g., in the treatment ofbipolar depression, cognition associated with schizophrenia, andexcessive sleepiness and fatigue in conditions such as Parkinson'sdisease and cancer.

The dosages of a Compound of Formula I and/or the second therapeuticagents of Method I-A and II-A can be the same as or lower than theapproved dosage for the drug, the clinical or literature test dosage orthe dosage used for the drug as a monotherapy. In a preferredembodiment, the dosages of a Compound of Formula I and/or the secondtherapeutic agents of Method I-A and II-A are lower than when used in amonotherapy. Therefore, in a particular embodiment, the dosage of aCompound of Formula I is lower than 100 mg once daily, preferably lessthan 50 mg, more preferably less than 40 mg, still more preferably lessthan 30 mg, still more preferably less than 20 mg, still more preferablyless than 10 mg, still more preferably less than 5 mg, most preferablyless than 2.5 mg. In particular embodiments, the second therapeuticagent of Method I-A and II-A is doxepin and the dosage of doxepin isbetween about 0.001 mg and 49 mg. Preferably, the amount of doxepin isbetween about 0.0001 mg and 20 mg, between about 0.001 mg and 10 mg,more preferably between about 0.01 mg and 9 mg, and still morepreferably between about 0.01 mg and 6 mg.

In another preferred embodiment, the dosages of both the Compound ofFormula I and the second therapeutic agent of Method I-A and II-A arelower than the dosages used for the individual drug as a monotherapy.Therefore, in a particular embodiment, for example, Method I-A or II-Acomprises administering (1) a Compound of Formula I at a dosage lowerthan 100 mg once daily, preferably less than 50 mg, more preferably lessthan 40 mg, still more preferably less than 30 mg, still more preferablyless than 20 mg, still more preferably less than 10 mg, still morepreferably less than 5 mg, most preferably less than 2.5 mg; and (2)doxepin at a dosage of less than 50 mg, more preferably, less than 20mg, still more preferably, less than 10 mg, most preferably less than 6mg, in free or pharmaceutically acceptable salt form. In an especiallyembodiment, Method I-A or II-A comprises administering to a patient inneed thereof (1) a Compound of Formula I at a dosage of less than 5 mg,more preferably less than 2.5 mg; and (2) doxepin at a dosage of lessthan 10 mg, preferably less than 6 mg, in free or pharmaceuticallyacceptable salt form.

In some preferred embodiments, Method I-A or II-A is a method for thetreatment of sleep disorders associated with psychosis, e.g., sleepdisorders associated with schizophrenia or Parkinson's disease. Inanother preferred embodiment, Method I-A or II-A is a method for thetreatment of psychosis, e.g., schizophrenia or Parkinson's disease inpatients suffering from insomnia. In still another preferredembodiments, Method I-A or II-A is a method for the treatment of one ormore sleep disorders.

The term “conventional antipsychotic agents” or “conventionalantipsychotic drugs” or “antipsychotic agents” include, but are notlimited to droperidol, fluphenazine, loxapine, mesoridazine molidone,perphenazine, pimozide, prochlorperazine promazine, thioridazine,thiothixene, trifluoperazine, clozapine, aripiparazole, olanzapine,quetiapine, risperidone and ziprasidone. Other conventionalantipsychotic agents also include chlorpromazine, haloperidol andpaliperidone. Conventional antipsychotic agents are divided into typicaland atypical antipsychotic agents. Typical antipsychotic agents includebut are not limited to chlorpromazine, droperidol, fluphenazine,haloperidol, loxapine, mesoridazine molidone, perphenazine, pimozide,prochlorperazine promazine, thioridazine, thiothixene andtrifluoperazine. Atypical antipsychotic agents include but are notlimited to clozapine, aripiparazole, olanzapine, quetiapine,risperidone, ziprasidone, and paliperidone. Therefore, patients who areunable to tolerate the side effects of conventional antipsychotic agentsrefer to patients who are unable to tolerate the side effects of theagents as described above. Consequently, such patients would benefitfrom a monotherapy of a Compound of Formula I (e.g., Method I), whereinCompound of Formula I targets 5HT2A receptors without or with minimalinteraction with D₂ receptors. In addition, these patients would alsobenefit from a combination therapy comprising a Compound of Formula Iand one or more second therapeutic agents (e.g., Method I-A or II-A)wherein the dosages of the second agent(s) or both the second agents andthe Compound of Formula I are lower than when they are administered as amonotherapy. As such, undesirable side effects may be reduced orminimized.

The term “GABA” refers to gamma-aminobutyric acid. The GABA compounds ofMethod I-A or II-A are compounds which bind to the GABA receptor, andinclude, but are not limited to one or more of doxepin, alprazolam,bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam,flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam,triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem,gabaxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals) orestazolam.

Additional 5HT2a antagonist of Method I-A or II-A include, but are notlimited to, one or more of ketanserin, risperidone, eplivanserin,volinanserin (Sanofi-Aventis, France), pruvanserin, MDL 100907(Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (ArenaPharmaceuticals, San Diego, Calif.), or AVE8488 (Sanofi-Aventis,France).

The 5HT1a agonist may be, for example, one or more of repinotan,sarizotan, eptapirone, buspirone or MN-305 (MediciNova, San Diego,Calif.).

The melatonin agonist of Method I-A or II-A include, but are not limitedto, one or more of melatonin, ramelteon (ROZEREM®, TakedaPharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville,Md.), PD-6735 (Phase II Discovery) or agomelatine.

The ion channel blocker of Method I-A or II-A include, but are notlimited to, one or more of lamotrigine, gabapentin or pregabalin.

The orexin receptor antagonist of Method I-A or II-A include, but arenot limited to, one or more of orexin, a 1,3-biarylurea, SB-334867-a(GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline) or a benzamidederivative, for example.

The serotonin-2 antagonist/reuptake inhibitor (SARI) of Method I-A orII-A include, but are not limited to, one or more of Org 50081(Organon-Netherlands), ritanserin, nefazodone, serzone or trazodone.

The neurokinin-1 drug of Method I-A or II-A includes, but are notlimited to, Casopitant (GlaxoSmithKline).

The term “antidepressant” or “other antidepressant” may includeamitriptyline, amoxapine, bupropion, citalopram, clomipramine,desipramine, doxepin, duloxetine, escitaloprame, fluoxetine,fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine,nefazodone, nortriptyline, paroxetine, phenlzine sulfate, protiptyline,sertraline, tranylcypromine, trazodone, trimipramine, velafaxine, infree or pharmaceutically acceptable salt forms.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular Compound of the Invention used, the mode ofadministration, and the therapy desired. Unless otherwise indicated, anamount of the Compound of the Invention for administration (whetheradministered as a free base or as a salt form) refers to or is based onthe amount of the Compound of the Invention in free base form (i.e., thecalculation of the amount is based on the free base amount). Compoundsof the Invention may be administered by any suitable route, includingorally, parenterally or transdermally, but are preferably administeredorally. In general, satisfactory results for Method I or any of1.1-1.37, e.g. for the treatment of a combination of diseases such as acombination of at least depression, psychosis, e.g., (1) psychosis,e.g., schizophrenia, in a patient suffering from depression; (2)depression in a patient suffering from psychosis, e.g., schizophrenia;(3) mood disorders associated with psychosis, e.g., schizophrenia, orParkinson's disease; and (4) sleep disorders associated with psychosis,e.g., schizophrenia, or Parkinson's disease, as set forth above areindicated to be obtained on oral administration at dosages of the orderfrom about 1 mg to 100mg once daily, preferably 2.5 mg-50 mg, e.g., 2.5mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg, once daily, preferablyvia oral administration. Satisfactory results for Method II or any of2.1-2.19, e.g. for the treatment of sleep disorder alone are indicatedto be obtained on oral administration at dosages of the order from about2.5 mg-5 mg, e.g., 2.5 mg, 3 mg, 4 mg or 5 mg, of a Compound of FormulaI, in free or pharmaceutically acceptable salt form, once daily,preferably via oral administration. Satisfactory results for Method I-Aare indicated to be obtained at less than100 mg, preferably less than 50mg, e.g., less than 40 mg, less than 30 mg, less than 20 mg, less than10 mg, less than 5 mg, less than 2.5 mg, once daily. Satisfactoryresults for Method II-A are indicated to be obtained at less than 5 mg,preferably less than 2.5 mg.ss

The phrase “pharmaceutically acceptable salts” refers to derivatives ofthe above disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the Compounds of the Inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free base forms of these compounds witha stoichiometric amount of the appropriate acid in water or in anorganic solvent, or in a mixture of the two; generally, nonaqueous medialike ether, ethyl acetate, ethanol, isopropanol, or acetonitrile arepreferred. Further details for the preparation of these salts, e.g.,toluenesulfonic salt in amorphous or crystal form, may be found inPCT/US08/03340 and/or U.S. Provisional Appl. No. 61/036,069.

Pharmaceutical compositions comprising Compounds of the Invention may beprepared using conventional diluents or excipients and techniques knownin the galenic art. Thus oral dosage forms may include tablets,capsules, solutions, suspensions and the like.

EXAMPLES Example 1: Binding Assay for 5-HT2A, Dopamine D₂, SERT, αA1,5-HT2C and H1 Receptors

Binding studies for 5-HT2A, dopamine D₂, SERT, αA1, 5-HT2C and H1receptors are well known in the art and may be used to determine thebinding affinities of the Compounds of the Invention. A Compound ofFormula I, 1-(4-Fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9, 10,10a-hexahydro-1H, 7H-pyrido[3′,4′, 4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (Compound A) is selected for detailedevaluation. The compound exhibits binding affinity profiles for 5-HT2A,D2, SERT, αA1, 5-HT2C and H1 as disclosed in Table 1 and Table 2compared to known antipsychotic agents.

A representative method for performing the binding studies may be foundin Fitzgerald et al., J. Neurochem. 1999 May; 72(5): 2127-34, thedisclosure of which is incorporated by reference.

1-(4-[125I] iodo-2,5-dimethxoyphenyl)-2-aminopropane([125] DOI; 2, 200Ci/mmol), N-[3H]methylspiperone (50 Ci/mmol), [3H]Prazosin (77 Ci/mmol),and lysergic acid diethylamide(N-methyl-[3H]([3H]-LSD; 73 Ci/mmol) werepurchased from New England Nuclear (Boston, Mass., U.S.A.) [3H]8-hydoxy-DPAT (217 Ci/mmol) and [3H]Mesulergine (50 Ci/mmol) werepurchased from Pharmacia Amersham (Arlington Heights, Ill., U.S.A.). Allother reagents were purchased from Research Biochemical International(Natick, Mass., U.S.A.), Sigma Chemical Co. (St. Louis, Mo., U.S.A.) orGibcoBRL unless otherwise noted.

Membrane receptors: Cell lines stably expressing recombinant human5-HT2A receptors were generated by calcium phosphate mediatedtransfection with plamids containing receptor cDNAs (Fitzgerald et al.,1999)

Stable expression of 5-HT2A and 5-HT2C receptors in human embryonickidney 293 Epstein-Barr nuclear antigen (HEK293E) cells. Stable celllines were generated by transfecting HEK293E cells with plasmidscontaining human 5-HT2A or 5-HT2C (VNV edited isoform cDNA using calciumphosphate. These plasmids also contained the cytomegalovirusintermediate early promoter to drive receptor expression, Epstein-Barvirus oriP for their maintenance as an extrachromosomal element, and thehph gene from Escherichia coli to yield hygromycin B resistance (Horlicket al, 1997; Rominger et al., 1998). Transfected cells were maintainedin Dulbecco's modified Eagle's medium (DMEM) containing dialyzed 10%fetal bovine serum at 37 degrees Celsius in a humid environment (5% CO2)for 10 days. The 5-HT2A cells were adapted to spinner culture for bulkprocessing, whereas it was necessary to maintain the 5-HT2C line asadherent cultures. On the day of harvest, cells were washed inphosphate-buffered saline, counted and stored at −80 degrees Celsius.

Membrane preparations On the day of assay, pellets of whole cells(containing 1×10⁸ cells expressing the receptor of interest were thawedon ice and homogenized in 50 mM Tris-HCL (ph 7.7) containing 1.0 mM EDTAusing a Brinkmann Polytron (PT-10; setting of 6 for 10s). The homogenatewas centrifuged at 48,000 g for 10 minutes, and the resulting pellet waswashed twice by repeated homogenization and centrifugation steps. Thefinal pellet was resuspended in tissue buffer, and protein content wasdetermined by the method of Bradford (1976) using bovine serum albuminas the standard.

Tranfected HEK293 cells (adherent) expressing human 5-HT2B and 5-HT1Areceptors provided membrane source for these assays. Cell linesexpressing rat D2-short and human D4 receptors were generated by calciumphosphate mediated transfection of Chinese hamster ovary (CHO) cellswith plasmids containing receptor cDNAs. Membranes prepared from ratfrontal cortex and frozen liver were used for alpha-1A and alpha-1Badrenergic receptor binding.

Measurement of agonist and antagonist radioligand binding to 5-HT2A and5-HT2C receptors

N-[3H] Methylspiperone and [3H] mesulergine were used as the antagonistradioligands for the 5HT2A and 5HT2C receptors, respectively, whereas[125]DOI was used as the agonist radioligand for both receptors. Thehigh efficacy partial agonist [125]DOI was chosen over the full agonist[3H]-5HT because [3H]-5HT gave inadequate levels of specific bindingwith the lower density 5-HT2C line. In addition, the relatively weakbinding affinity of 5-HT for the 5-HT2A receptor precluded its use as aradioligand. Equilibrium binding conditions for each radioligand at eachreceptor were established and optimized with respect to time,temperature, and protein concentration before saturation and competitionexperiments were conducted.

For the agonist radioligand binding studies, assays were conducted indisposable polypropylene 96-well plates (Costar Corporation, Cambridge,Mass., U.S.A.) and were initiated by addition of membrane homogenate intissue buffer (10-30 micrograms per well.) to assay buffer (50 mMTris-HCL, 0.5mM EDTA, 10 mM pargyline, 10 mM MgSO4, and 0.05% ascorbicacid, pH 7.5) containing [125]DOI (final concentration, 0.3-.0.5 nM withor without competing ligand. The reaction mixture was incubated toequilibrium for 45 min at 37 degrees Celsius and terminated by rapidfiltration (cell harvester, Inotech Biosystems, Lansing, Mich., U.S.A.)over GFF glass filter membranes that had been presoaked in 0.3%polyethylenimine. Filters were washed in ice-cold 50 mM Tris-HCL buffer(ph 7.5) and then counted for radioactivity in a gamma counter at 80%efficiency. For saturation studies, 14 concentrations of [125I]DOI up toa maximal concentration of 6 nM were used. Specific binding at eachconcentration was determined in the presence of 10 micromolar mianserin.For competition experiments, a fixed concentration of [125]DOI (0.3-5nM) was competed with duplicate concentrations of ligand (12concentrations ranging from 10 picomolar to 10 micromolar).

For the antagonist radioligands, saturation experiments for [3H]mesulergine and N-[3H]methylspiperone were conducted to establish theequilibrium binding parameters of these radio-ligands for the 5-HT2C and5-HT2A receptors, respectively. The assay buffer used in the [3H]mesulergine assays was identical to that used in the [125I] DOI assayexcept for the addition of 10 mM CaCl2 for 10 mM MgSO4. The assay bufferused for the N-[3H]methylspiperone assays was identical to that in the[125I] DOI assay except for the exclusion of 20 mM NaCl. 5-HT2C membranehomogenate (40 micrograms of protein per well) was incubated with 14concentrations of [3H]mesulergine (up to a final concentration of 20 nMfor 45 minutes at 37 degrees Celsius. For the 5-HT2A assay, membranehomogenate (40 micrograms of protein per well) was incubated with 14concentrations of N-[3H] methylspiperone for 30 minutes at 37 degreesCelsius. Excess (10 micromolar) mianserin or ketanserin was used todefine nonspecific binding in the 5-HT2C and the 5-HT2A assays,respectively. Assays were conducted and terminated as described for theagonist radioligand assays except that the filters were counted forradioactivity by liquid scintillation spectroscopy.

Data Analysis

The equilibrium disassociation constants (Kd values) and maximal numberof binding sites (Bmax values) from the saturation experiments andapparent dissociation constants (Ki values) from the competitionexperiments were calculated using an iterative nonlinear regressioncurve-fitting program (GraphPad Prism, San Diego, Calif., U.S.A.)

TABLE 1 Receptors Compound A* Haloperidol Aripiprazole ClozapineOlanzapine Quetiapine Risperidone Ziprasidone K_(i) (nM) 5-HT2A 0.54 1009 9.6 2.5 202 0.5 0.28 D₂ 31.9 0.7 1.6 190 31 400 5.9 5 SERT33-72 >1,000 240-405 >1,000 >10,000 >1,000 ~1,000 112 (cloned) >1,000(platelet) α1A 73 11 26 19 60 20 2.3 6 5-HT2C 173 3949 130 13 7.1 200063 10 H1 >100 780 28 1 2 10 14 15

TABLE 2 SERT Activities of selected Compounds of the Invention comparedto other Antipsychotic agents Human platelet Rat forebrain Recombinantmembrane synaptosomal human binding membrane SERT in using binding CHOcell ³H—N- with membranes methyl- ³H—N-methyl- binding CitalopramCitalopram ³H-IMI K_(i) (nM) Compound A 72 46 33 Aripiprazole 405 207240 Risperidone 10,000 10,000 Olanzapine 10,000 >10,000 Reference IMIIMI IMI Reference Value 10.6 44 2.7 Reference Value 7.1 41 Repeated

Example 2: Effectiveness of the Compounds of Formula I as Antidepressantin Chronic Animal Model of Depression.

Experimental procedure for Table II:

Two different assays used to characterize affinity for the serotonintransporter were conducted at Caliper Life Sciences (Hopkinton, Mass.),a company that acquired NovaScreen. One assay (#100-0056), TransporterSERT, was a radioligand binding assay in rat forebrain using[3H]-N-Methyl-Citalopram as the radioligand at a concentration of 0.7nM. [3H]-N-Methyl-Citalopram has a Kd (binding affinity) of 1.7 n and aBmax of 33.1 fmol/mg protein. The assay was validated using thefollowing reference agent, imipramine (IMI) (Ki=40.9 nM). Otherreference agents which may be used include paroxetine (Ki=0.1 nM);fluoxetine (Ki=1.4 nM); clomipramine (Ki=2.8 nM), serotonin (Ki=55.6nM), and zimeldine (Ki=68.3 nM).

The other assay, Transporter SERT (h) was a radioligand binding assay inhuman platelets using [3H]-N-Methyl-Citalopram as a radioligand at aconcentration of 0.7 nM. In this assay, the Kd for[3H]-N-Methyl-Citalopram was 2.5 nM with a Bmax of 425 fmol/mg protein.The assay was validated using clomipramine (Ki=0.2 nM), citalopram(Ki=3.0 nM), and imipramine (Ki=4.0 nM).

The third assay was conducted at Cerep (Celle L'Evescault, France). Thethird assay was a radioligand binding assay in human recombinantserotonin transporter in CHO cells using [3H]-imipramine as theradioligand at a concentration of 2 nM. The assay was validated withunlabeled imipramine. (Ki=2.7 nM).

EXPERIMENTAL DESIGN: Anti-depressant activity of a Compound of Formula I(Compound A) is measured using the social defeat (resident-intruder)mouse model for depression in which induced social withdrawal in rodentshas been shown to be responsive to chronic, but not acute,anti-depressant drug treatment. The social defeat paradigm is based onthe observation that psychosocial stress produces long-lastingalterations in the motivation of mice for social contact. Mice aresubjected to a 10 day training period in which they are exposed to dailybouts of social stress, i.e., exposure to a different aggressive mouse(‘aggressor’) each day. They are then observed for their social behaviorby measuring their tendency to approach an unfamiliar mouse, i.e., tospend time in the “Interaction Zone” which is in close proximity to theunfamiliar intruder. Mice are recorded by videotape and scored forsocial behavior (i.e., time in the Interaction Zone) and aversivebehavior (i.e., time in the Corner Zones). Whereas normal mice displaysocial interactions with unfamiliar mice (i.e., spend more time in theInteraction Zone), those mice exposed to repeated social defeatconditions display aversive reactions (i.e., spend more time in theCorner Zones) and spend less time than normal mice in contact with theunfamiliar test mouse (i.e., resident intruder or TARGET).

The aversive responses of ‘socially defeated’ mice are resilient;aversive behavior persists for weeks and can be elicited even 4 weeksafter the end of the 10 day social stress exposure. The aberrantbehavior of ‘socially defeated’ mice is responsive to chronicanti-depressant medications. Mice treated daily for 30 days with theanti-depressant drugs, fluoxetine or imipramine, display improved socialinteraction behavior (i.e., spend more time in the Interaction Zoneversus the Corner Zones) when once again exposed to an unfamiliar mouse.Notably, chronic, but not acute, fluoxetine treatment improves socialbehavior. Since social behaviors measured by the social defeat paradigm,like human depression, are differentially responsive to chronicanti-depressant therapy, this paradigm may more accurately reflectbeneficial actions of novel anti-depressant therapies, providing anadvantage over traditional models (such as, Forced Swim and TailSuspension models) that respond to acute pharmacological effects ofdrugs that are not necessarily predictive of chronic antidepressantefficacy.

A representative compound of the present invention, Compound A, istested in the social defeat paradigm. Normal male mice or mice subjectedto social defeat stress once daily for 10d (N=8-12 C57B1/6 mice/group)are injected once daily for 29d Compound A (1 mg/kg, IP) or vehiclesolution (5% DMSO/5% Tween-20/15% PEG400/75% water). On day 30, all miceare tested for their social response to an unfamiliar mouse. Normal micetreated with Compound A once daily for 30d are healthy andnormal-appearing and gained weight normally. These mice spend comparabletime in the Interaction Zone as mice receiving the vehicle injection. Asanticipated, mice that are subjected to 10d of social stress showedprofound social defeat behavior, spending less than half the amount oftime in the vicinity of an unfamiliar mouse than normal un-stressedmice. Socially-defeated mice treated chronically with Compound A,however, exhibited a significant increase in social behavior, spendingalmost twice as much time in the Interaction Zone when exposed to anunfamiliar mouse compared with socially-defeated mice receiving vehicleinjections. Thus, the amount of time spent in the Interaction Zone bysocially-defeated mice receiving Compound A is indistinguishable fromnormal mice receiving vehicle injections. Thus, socially-defeated micespend significantly more time in the distant Control Zone(s) comparedwith normal (non-stressed) mice. The administration of a compound of thepresent invention significantly reverses this behavioral preference.

Taken together, these data demonstrate that daily administration ofCompound A induce a behavioral response in socially-stressed miceconsistent with antidepressant efficacy and comparable to that elicitedby anti-depressant medications such as fluoxetine.

Example 3: Effectiveness in Alleviating L-Dopa Induced Dyskinesia

Reduction in axial, orolingual and limb abnormal involuntary movementsusing standard Abnormal Involuntary Movement Scale (AIMS) in dyskinesicmice injected daily with the compound in combination with L-DOPAindicates that co-administration of Compounds of Formula I reducesdevelopment and expression of AIMS associated with dyskinetic behavior(orolingual, axial, and limb) and locomotor activity (locomotive AIMS).Unilateral 6-OHDA-lesioned mice are administered a Compound of Formula I(Compound A) in accordance with the following schedule:

Control:

Day 1—Day 9: Treatment with L-DOPA/benserazide

Day 10: Treatment with L-DOPA/benserazide+Evaluation of AIMs(dyskinesia)

EXPERIMENT 1 (Chronic): Development of Dyskinesia

Day 1-Day 10: Treatment with L-DOPA/benserazide plus ITI-007 ITI-007PD.

Day 11: Treatment with L-DOPA/benserazide+Evaluation of AIMs(dyskinesia)

EXPERIMENT 2 (Acute): Expression of Dyskinesia

Day 1-Day 10: Treatment with L-DOPA/benserazide

Day 11: Treatment with L-DOPA/benserazide plus ITI-007+Evaluation ofAIMs (dyskinesia)

Compound A (0.3 mg/kg IP) reduces dyskinetic behaviors after chronicco-administration with levodopa (10 mg/kg IP) to unilateral6-OHDA-lesioned mice. The compound effectively reduces (by ˜50%) thedevelopment of dyskinetic behaviors in PD mice (i.e., Chronic treatmentgroup). It has a less robust but still significant effect (by ˜25%reduction) on established dyskinetic behaviors (i.e., Acute treatmentgroup). Taken together, these data suggest that Compounds of Formula Ihave utility for the prevention and treatment of L-DOPA-induceddyskinesias in PD. In addition to reducing L-DOPA-Induced Dyskinesias,as described above, the Compounds of Formula I will also reduce PDpsychosis and depression, improve poor night time sleep and reduceexcessive daytime sleepiness.Example 4—Clinical Trial for Low Dose for Sleep Maintenance Insomnia andSleep Disorders Associated with Psychiatric and Neurological Diseases

As described above, at low doses, Compounds of Formula I are primarilyserotonin 5-HT2A antagonists. At higher doses, the compounds also act asa pre-synaptic partial agonist, post-synaptic antagonist at D2 dopaminereceptors and inhibits the serotonin transporter. The present studyevaluates a range of doses of a Compound of Formula (Compound A) inpatients with sleep maintenance insomnia (SMI). The main objectives ofthis study are to determine if the compound decreases wake time aftersleep onset (WASO) as a measure of sleep maintenance efficacy and if thecompound increases slow wave sleep (SWS) as a biomarker for 5-HT2A brainreceptor occupancy.

The study is a randomized, double-blind, complete cross-over design.Eighteen patients experiencing SMI, aged 18 to 65, are included in theefficacy analysis. All subjects receive three single doses of Compound Aand placebo, administered in the evening before overnight PSG recordingswith one week washout between doses. SWS, WASO, other PSG measures, andsafety are analyzed.

Compound A dose-dependently decreases WASO (p=0.032) and increases SWS(p=0.002). Compound A preserves normal sleep architecture over thecourse of the night. Compound A is safe and well tolerated. Compound Adose-dependently and robustly decreases WASO in patients with SMI,suggesting efficacy for improved sleep maintenance. The magnitude ofeffect on WASO at the highest tested dose suggests that the uniquepharmacological profile of Compounds of Formula I is useful inmaintaining sleep above and beyond that provided by 5-HT2A antagonism.In addition, increases in SWS sleep suggest that significant occupancyof brain 5-HT2A receptors is occurring. Compounds of Formula I areuseful for patients with SMI and for the treatment of sleep disordersassociated with psychiatric and neurological diseases.

Improved Sleep as Measured by PSG (Sleep Efficiency defined as timeasleep/time in bed)

Dose- Response Outcome Trend Measure Mean Change from Baseline (min)Analysis (n = 18) Placebo 1 mg 5 mg 10 mg p-value SWS −3.75 0.47 5.538.94 p = 0.002 WASO −1.86 −12.69 −14.31 −33.22 p = 0.001 Total Sleep−9.22 4.17 0.56 27.61 p < 0.001 Time Total Time 9 −4.08 −1.42 −28.31 p <0.001 Awake Sleep −1.94 0.82 0.14 5.80 p < 0.001 Efficiency

The compound causes no change on latency to REM (p=0.143) and no changein duration of REM (p=0.124). The compound does not impair latency tofall asleep (p=0.455). The compound increases slow wave sleep during thefirst half of the night (first quarter p=0.022; second quarter p=0.029)and increases stage 2 sleep during the second half of the night (thirdquarter p=0.048, fourth quarter p=0.004). The compound is safe andwell-tolerated in patients with sleep maintenance insomnia. There are noserious adverse events. There are no dose-related adverse events orchanges in safety parameters. The compound does not impair cognitivefunction as measured in the morning after PSG by the Digit SymbolSubstitution Test (DSST), the Word Pair Associates Test (WPAT), or theLeeds Psychomotor Test.

Striatal D2 receptor occupancy in healthy volunteers using positronemission tomography is dose dependent. The doses evaluated for sleepdisorder are shown to be below doses where there is high striatal D2occupancy.

Dose 10 mg 20 mg 30 mg % Striatal D2 Occupancy ~12% ~20% ~32%

1-17. (canceled)
 18. A method for the treatment of one or more sleepdisorders comprising administering to a patient in need thereof aCompound of Formula I:

wherein X is O, —NH or —N(CH₃); and Y is —O— or —C(O)—, in free orpharmaceutically acceptable salt form, wherein the amount of saidCompound of Formula I administered is from 0.1 mg to 20 mg, in free orpharmaceutically acceptable salt form, provided that in the case of asalt, the weight is calculated as the free base.
 19. (canceled)
 20. Themethod according to claim 18, wherein the sleep disorder is sleepmaintenance insomnia.
 21. The method according to claim 18, furthercomprising one or more therapeutic agents selected from the groupconsisting of compounds that modulate GABA activity, a GABA-B agonist, a5-HT modulator, a melatonin agonist, an ion channel modulator, aserotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin receptorantagonist, an H3 agonist, a noradrenergic antagonist, a galaninagonist, a CRH antagonist, human growth hormone, a growth hormoneagonist, estrogen, an estrogen agonist, a neurokinin-I drug, ananti-depressant, and an antipsychotic agent e.g., in free orpharmaceutically acceptable salt form.
 22. The method according to claim18, further comprising administering one or more therapeutic agentsselected from the group consisting of modafinil, armodafinil, doxepin,alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam,flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam,temazapam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon,Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT 201, estazolam,ketanserin, risperidone, eplivanserin, volinanserin, pruvanserin, MDL100907, HY10275, APD125, AVE8488, repinotan, sarizotan, eptapirone,buspirone, MN-305 melatonin, ramelteon, VEC-162, PD-6735, agomelatine,lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea,SB-334867-a, GW649868, a benzamide derivative, Org 50081, ritanserin,nefazodone, serzone, trazodone, Casopitant, amitriptyline, amoxapine,bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine,escitaloprame, fluoxetine, fluvoxamine, imipramine, isocarboxazid,maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine,phenlzine sulfate, protiptyline, sertraline, tranylcypromine, trazodone,trimipramine, velafaxine, chlorpromazine, haloperidol, droperidol,fluphenazine, loxapine, mesoridazine molidone, perphenazine, pimozide,prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine,clozapine, aripiparazole, olanzapine, quetiapine, ziprasidone andpaliperidone, in free or pharmaceutically acceptable salt form. 23-26.(canceled)
 27. The method of claim 18 wherein the sleep disorder isinsomnia in a patient suffering from depression. 28-39. (canceled) 40.The method of claim 18 wherein the sleep disorder is insomnia in apatient suffering from psychosis.
 41. The method of claim 18 wherein thesleep disorder is insomnia in a patient suffering from schizophrenia.42. The method of claim 18 wherein the sleep disorder is insomnia in apatient suffering from Parkinsons disease.
 43. The method of claim 18wherein the Compound of Formula I is in the form of the tosylate salt.44. The method of claim 20 wherein the Compound of Formula I is in theform of the tosylate salt.
 45. The method of claim 27 wherein theCompound of Formula I is in the form of the tosylate salt.
 46. Themethod of claim 40 wherein the Compound of Formula I is in the form ofthe tosylate salt.
 47. The method of claim 41 wherein the Compound ofFormula I is in the form of the tosylate salt.
 48. The method of claim42 wherein the Compound of Formula I is in the form of the tosylatesalt.